Intermediate compounds and methods

ABSTRACT

The present invention relates to compounds of (II) and an acceptable salt or hydrate thereof method of making same.

FIELD OF THE INVENTION

This invention relates to novel intermediates and methods of makingthem.

BACKGROUND OF THE INVENTION

Substituted hydrazine intermediates, with the general structure shownbelow, are versatile intermediates and nucleophiles useful for makingheterocyclic compounds such as pyrazoles, and pyridazines as well aspesticides and pharmaceuticals (see, e. g. Kulkami et al. Chem Biol.Drug Des 2014 (84), 270-281, Aggarwal et al. Indian J. Chem. 2006, 45B,1426-1430, Liu et al. Tetrahedron 2015, 7658-7662).

In particular, hydrazines substituted with alkyl, cycloalkyl andspirocyclic rings have found recent use in novel pharmaceuticalapplications directed towards treatment of immunology and oncologydisorders (e.g. WO 2016115356, U.S. Pat. No. 9,156,847 B2).Consequently, there remains a need for additional derivatives ofhydrazine that may be useful in the synthesis of pharmacologicallyrelevant compounds.

SUMMARY OF THE INVENTION

The invention relates to novel intermediate compounds and methods fortheir preparation.

In a first aspect, the present invention relates to an intermediatecompound of formula (II):

wherein R3 is chosen from hydrogen, halogen, halo C1-4 alkyl, C1-4alkyl, C1-4 alkoxy, —CN, halo C1-4 alkoxy, acyl, acyloxy, alkylaryl orcycloalkyl; and R4 is hydrogen, halogen, halo C1-4 alkyl, C1-4 alkyl,C1-4 alkoxy, aryloxy, cycloalkyl, alkylaryl; or an acceptable salt orhydrate thereof.

In a second aspect, the present invention relates to a process forpreparing the compound of formula (II) comprising the steps of:

-   -   (i) Converting a compound of formula F to a compound of formula        F1

-   -   (ii) Coupling of a compound of formula F1 with compound F2 and        conversion through additional steps to a compound of formula F3

-   -   (iii) Conversion of compound F3 through additional steps to a        compound of formula F4

-   -   (iv) Conversion of compound F4 to a compound of formula F5

-   -   (v) Conversion of compound F5 through additional steps to a        compound of formula F6

-   -   (vi) Conversion of compound F6 to a compound of formula II

-   -   -   wherein R3 is chosen from hydrogen, halogen, halo C1-4            alkyl, C1-4 alkyl, C1-4 alkoxy, —CN, halo C1-4 alkoxy, acyl,            acyloxy, alkylaryl or cycloalkyl; and R4 is hydrogen,            halogen, halo C1-4 alkyl, C1-4 alkyl, C1-4 alkoxy, aryloxy,            cycloalkyl, alkylaryl; or an acceptable salt or hydrate            thereof.

DETAILED DESCRIPTION OF THE INVENTION

Substituted hydrazine intermediates are versatile intermediates andnucleophiles useful for making heterocyclic compounds such as pyrazoles,and pyridazines as well as pesticides and pharmaceuticals However, theinventors are not aware of any publications that teach the compounds ofthe present invention and their use for large-scale commercialproduction of pyrazoles or pyridazines.

All terms as used herein in this specification, unless otherwise stated,shall be understood in their ordinary meaning as known in the art. Othermore specific definitions are as follows:

K₂CO₃=potassium carbonate

MeCN=acetonitrile

NaOH=sodium hydroxide

iPr₂EtN=ethyl diisopropylamine

POCl₃=phosphorous oxychloride

NaOMe=sodium methoxide

MeOH=methanol

NHBoc=tert-butoxycarbonyl protecting group

BocN=tert-butoxycarbonyl protecting group

BuOH=1-butanol

Ms=methanesulfonyl; mesylate

IBCF=isobutyl chloroformate

NMM=4-methylmorpholine (N-methyl morpholine)

EtOH=ethanol

Protecting group=tert-butoxycarbonyl (Boc), phenoxycarbonyl (Cbz)

The term “(C₁-C₄)alkyl” refers to branched and unbranched alkyl groupshaving from 1 to 4 carbon atoms. Examples of —(C₁-C₄)alkyls includemethyl, ethyl, n-propyl, isopropyl, n-butyl. It will be understood thatany chemically feasible carbon atom of the (C₁-C₄)alkyl group can be thepoint of attachment to another group or moiety.

The term “halo” or “halogen” refers to fluoro, chloro, bromo or iodo.

In all alkyl groups or carbon chains one or more carbon atoms can beoptionally replaced by heteroatoms: O, S or N, it shall be understoodthat if N is not substituted then it is NH, it shall also be understoodthat the heteroatoms may replace either terminal carbon atoms orinternal carbon atoms within a branched or unbranched carbon chain. Suchgroups can be substituted as herein above described by groups such asoxo to result in definitions such as but not limited to: alkoxycarbonyl,acyl, amido and thioxo.

Certain compounds used in the processes of the invention may exist assalts formed from inorganic and organic acids. Such acids may beemployed in preparing and/or isolating certain intermediates. Forconvenience, such acids are referred to herein as “salt-forming acids”and the salts formed from such salt-forming acids are referred to hereinas “salt adducts.” A non-limiting example of a useful salt-forming acidis oxalic acid.

As noted above, the invention relates in one embodiment to methods ofmaking the compounds of formula (II). Methods of making the compounds offormula (II) according to the invention are described below where the Rgroups are as defined above.

A nonlimiting method for making the compound of formula (II) accordingto the invention is depicted in Scheme 2 below.

1.1.1. General Procedure for the Synthesis of Compounds of Formula F1

To a 1 L Chemglass reactor equipped with mechanical stirrer, refluxcondenser, argon inlet and thermocouple with T_(jacket)=22° C. was addedcompound F (1.0 equiv.), p-toluenesulfonic acid monohydrate (0.03equiv.), Methanol HPLC Plus 99.9% (5 volumes) and Trimethylorthoformate(1.25 volumes). The resulting solution was heated at reflux(T_(batch)=52-53° C.) with T_(jacket)=65° C. for 1-2 hours. A sampleafter 1 h reflux analyzed by ¹H-NMR (0.075 mL rxn sample diluted with1.5 mL d⁶-DMSO) showed complete conversion. Distilled trimethylorthoformate and methanol at 50° C./<200 torr until no more solvent cameoff. Diluted with methyl tert-butyl ether (5 volumes) and washed organiclayer with 5% Na₂CO₃ (2.5 volumes) twice and once with aq. 3% NaCl (2.5volumes). The organic layer was concentrated at 50° C./<200 torr to givecompound F1 as a yellow oil in 90-95% yield.

methyl 3,3-dimethoxycyclobutane-1-carboxylate

¹H-NMR (DMSO-d⁶); δ 3.61 (s, 3H), 3.06 (s, 3H), 3.03 (s, 3H), 2.80-2.90(m, 1H), 2.33-2.42 (m, 2H), 2.17-2.25 (m, 2H). ¹³C-NMR (DMSO-d⁶); 174.6,99.3, 51.6, 48.1, 47.7, 34.9, 27.8.

1.2.1. General Procedure for the Synthesis of Compounds of Formula F3

To a 1 L reactor equipped with mechanical stirrer, thermocouple, refluxcondenser and argon inlet was added diisopropylamine (1.1 equiv.) andanhydrous tetrahydrofuran (5 volumes based on compound F1). The solutionwas stirred under argon and cooled to <−20° C. with T_(jacket)=−30° C.BuLi 2.5M hexanes (1.1 equiv.) was added slowly, keeping T_(batch)<−10°C. The light yellow solution of LDA was stirred for 10 min and thencompound F1 (1.0 equiv.) was added dropwise over 45-50 minutes, keepingT_(batch)<−20° C. The resulting orange solution was stirred atT_(jacket)=−30° C. for ca. 10 minutes. The [(2-iodoethoxy)methyl]benzene(F2) (1.0 equiv.) was added dropwise over ca. 10 minutes, leading to areddish orange solution. The addition was slightly exothermic and theinternal temperature rose to ca. −17° C. by the end of the addition. SetT_(jacket)=−20° C. and stirred. The exotherm continued for about 10minutes to ca. −6.4° C. when the internal temperature started todecrease. A yellow suspension formed within ˜60 minutes stirring atT_(jacket)=−20° C. The reaction was quenched with half-saturated NH₄Cl(5 volumes) after 2 hours stirring. Warmed reaction to room temperatureand separated layers. Washed organic layer with water (3.5 volumes) andconcentrated under reduced pressure at 40° C./100 mbar to a yellow oil.The oil was diluted with methanol (2.5 volumes based on compound F1) andtetrahydrofuran (2.5 volumes based on compound F1). The solution wasstirred under argon and a solution of lithium hydroxide hydrate (1.0equiv. based on Compound F1) in water (3 volumes based on Compound F1)was added in one portion. The mixture was stirred at T_(jacket)=75° C.for 2-3 hours after which HPLC analysis indicated complete hydrolysis ofthe ester. The batch was cooled and concentrated under reduced pressureat 40° C./100 mbar to remove MeOH and THF and reduce volume to about 40%of original. The residual oil was diluted with methyl tert-butyl ether(2 volumes based on compound F1) and filtered through a pad of Celite.The filter pad was rinsed with methyl tert-butyl ether followed by water(2 volumes based on compound F1). The mixture was allowed to settle andthe top organic layer was discarded. The aqueous layer was washed withmethyl tert-butyl ether (2 volumes based on compound F1) and the toporganic layer was discarded. Charged n-heptane (3.5 volumes based oncompound F1) and stirred the mixture. Added 2M aq. hydrochloric acid(˜0.4 equiv.) to reactor, and then added seeds. The temperature was setto T_(jacket)=5-7° C. and 2M aq. hydrochloric acid (˜0.3 equiv.) wascharged slowly over ca 20 minutes, keeping batch temperature <20° C.,until pH was ˜4. The suspension was cooled to ˜10° C. and stirred forabout 30 minutes. The slurry was filtered on a medium Buchner frit andthe cake washed with n-Heptane (0.5 volumes) followed by water (1.0volumes). The cake was dried on the frit with house-vacuum to afford60-62% yield of compound F3 as off-white sugar-like crystals.

1-(2-(benzyloxy)ethyl)-3,3-dimethoxycyclobutane-1-carboxylic acid

¹H-NMR (DMSO-d⁶); δ 12.3 (br s, 1H), 7.23-7.37 (m, 5H), 4.41 (s, 2H),3.39 (t, J=6.7 Hz, 2H), 3.03 (s, 3H), 3.00 (s, 3H), 2.44 (d, J=13 Hz,2H), 2.08 (d, J=13 Hz, 2H), 2.01 (t, J=6.7 Hz, 2H). ¹³C-NMR (DMSO-d⁶);177.0, 138.5, 128.2, 127.3, 98.5, 72.0, 66.7, 47.8, 47.7, 40.1, 37.3,36.4.

1.3.1. General Procedure for the Synthesis of Compounds of Formula F4

To a 1 L reactor equipped with mechanical stirrer, thermocouple, refluxcondenser and argon inlet was added CDI (66.11 g, 407.7 mmol mmol) andTHF (200 mL). A solution of compound F3 (100 g, 339.7 mmol) in THF (300mL) was added over about 20 min. The resulting solution was stirred atroom temperature for about 30 min. To another reactor, sodiumborohydride (12.85 g, 339.7 mmol) was charged followed by cold (−5° C.)water (400 mL). The solution was cooled to 2˜3° C. The THF solution wasthen charged over 15˜30 min, keeping internal temperature below 35° C.and the resulting mixture was stirred for about 20 min at 20˜35° C. Thereaction mixture was concentrated by vacuum distillation, keepinginternal temperature below 45° C., to half of its original volume. MTBE(400 mL) was charged and the mixture filtered to remove the solids. Thecake was rinsed with MTBE (50 mL) and water (50 mL). The combinedfiltrates were stirred for about 10 minutes and the layers separated.The bottom aqueous layer was drained. Aqueous 1M HCl (300 mL) was addedto the organic layer, the mixture stirred for 10 min the layersseparated. The bottom aqueous layer was drained. Aqueous 1M HCl (300 mL)was added and the mixture stirred for 2 h at 18˜22° C. The layers wereseparated and the bottom aqueous layer was drained. The organic layerwas washed with aqueous 5% Na₂CO₃ (200 mL) followed by 3% NaCl (200 mL).The reaction mixture was concentrated by vacuum distillation, keepinginternal temperature below 40° C., until about 15% of original volumeremained. to half of its original volume. Ethyl acetate (300 mL) wascharged and distillation continued until about 25% of original volumeremained. Ethyl acetate (300 mL) was charged and water contentdetermined using Karl-Fischer to make sure the amount was <0.1%. Repeatdistillation as necessary. To another reactor, Boc-hydrazine H₂NNHBoc(49.39 g, 373.7 mmol) and heptane (900 mL) were charged and stirred. Theethyl acetate solution was charged followed by acetic acid (10.20 g,169.9 mmol) and seed crystals of compound F4 (0.002 g). The resultingsuspension was stirred for about 30 min. The mixture was cooled to ˜5°C. and stirred for 30 min. The slurry was filtered and the cake washedwith 5:1 heptane/EtOAc (180 mL) and dried for 2 hours then in a vacuumoven at <40° C. to afford 85-90% yield of compound F4.

tert-butyl-2-(3-(2-(benzyloxy)ethyl)-3-(hydroxymethyl)cyclobutylidene)hydrazine-1-carboxylate

¹H-NMR (CDCl₃); δ 7.48 (br s, 1H), 7.27-7.37 (m, 5H), 4.50 (s, 2H),3.40-3.62 (m, 5H), 2.75 (d, J=16 Hz, 1H), 2.60-2.68 (m, 2H), 2.45 (d,J=16 Hz, 1H), 1.92 (t, J=5.3 Hz, 2H), 1.50 (s, 9H). ¹³C-NMR (CDCl₃);150.7, 137.4, 128.6, 128.0, 127.8, 81.1, 73.4, 68.1, 67.1, 41.9, 39.2,37.1, 37.0, 28.3.

1.4. General Procedure for the Synthesis of Compounds of Formula F5

To a 1 L reactor equipped with mechanical stirrer, thermocouple, refluxcondenser and argon inlet was added compound F4 (66.0 g, 1.0 equiv.) andTHF (6.0 V, 396 mL). The mixture was stirred and cooled to 0-5° C.Sodium bis(2-methoxyethoxy)aluminium hydride (Red-Al or Vitride) (127.3ml, 132.3 g, 2.4 equiv.) was added slowly over about 20 minutes, keepingbatch temperature <30° C. Note: Gas evolution was observed. When ca. ⅓to ½ of Red-Al had been added, the mixture turned quite viscous whilethe gas evolution continued with each drop of Red-Al. The mixture gotfairly thick. During the remaining addition the mixture gradually becameless viscous as the gas evolution diminished and the color turnedtowards yellow. At the end, a yellow thinner, readily stirrable solutionhad formed. The whole addition took ca 15-20 minutes. The mixture wasstirred under argon at 20-25° C. for at least 2-3 h and checked by HPLC.The batch was quenched into a 10 wt % aqueous solution of Rochelle salt(7.0 V, 560 mL), keeping batch temperature <30° C. The cloudy mixturewas stirred about 15 minutes and then allowed to separate for 15minutes. The lower aqueous layer was drained and the organic layerconcentrated at 40-45° C. batch temperature and vacuum to remove THF.Isopropyl acetate (6.0 V, 480 mL) and 10 wt % aqueous solution ofRochelle salt (7.0 V, 560 mL) were added and the mixture was stirred forabout 15 minutes at 45-50° C. and then allowed to separate for 15minutes. The lower aqueous layer was drained. Water (7.0 V, 560 mL) wasadded and the mixture was stirred 15-30 minutes at 45-50° C. and thenallowed to separate for 15 minutes. The lower aqueous layer was drainedand isopropyl acetate was distilled at 40-45° C. batch temperature andvacuum until about 3 V remains. Heptane (6.0 V, 480 mL) was added andthe mixture was warmed to 70-75° C. batch temperature to achievecomplete dissolution. The solution was cooled slowly to about 60° C.batch temperature and seeded. Slow cooling to 20-25° C. over at least 6hours gave a white slurry that was filtered on a medium Buchner frit.The cake was rinsed with n-heptane (160.00 ml; 1092.11 mmol; 2.00 V) anddried on the frit with house-vac for 1-2 hours and in a vacuum oven at35-40° C. for a minimum of 6 h to afford 50 g (74%) of compound F5 as awhite solid.

tert-butyl2-(3-(2-(benzyloxy)ethyl)-3-(hydroxymethyl)cyclobutyl)hydrazine-1-carboxylate

¹H-NMR (CDCl₃); δ 7.25-7.39 (m, 5H), 6.03 (br s, 1H), 4.50 (s, 2H), 3.99(br s, 1H), 3.45-3.58 (m, 5H), 3.30 (br t, J=6 Hz, 1H), 2.04-2.13 (m,2H), 1.84 (t, J=6 Hz, 2H), 1.52-1.60 (m, 2H), 1.45 (s, 9H). ¹³C-NMR(CDCl₃); 157.2, 137.7, 128.7, 128.1, 128.0, 80.7, 73.5, 69.2, 67.0,51.0, 40.3, 36.8, 35.5, 28.5.

1.5. General Procedure for the Synthesis of Compounds of Formula F6

To a reactor equipped with mechanical stirrer, thermocouple, refluxcondenser and argon inlet was added compound F5 (50.0 g, 142.67 mmol,1.0 equiv), Boc₂O (32.1 g, 145.53 mmol, 1.02 equiv) and EtOAc (200 mL, 4vol). The mixture was stirred and heated to 40-45° C. and stirred for 5hours after which LC analysis indicated complete reaction. The reactionwas cooled to 20-25° C. To a pressure reactor was added palladium oncarbon (3.0 g, 1.43 mmol) followed by the ethyl acetate solution of theboc-protected hydrazine derivative. The temperature was set to 25° C.the reactor purged with nitrogen and hydrogen. The reactor waspressurized with 50 psi of hydrogen and the contents stirred at 25° C.for 5 hours (the hydrogen uptake lasted for about 90 minutes). A samplewas analyzed by UPLCMS analysis to confirm complete conversion. Theethyl acetate solution was filtered through Celite and the cake washedwith additional ethyl acetate (approx. 2×50 mL, 2×1 vol). Distill ethylacetate under vacuum (˜120 mbar) at 45° C. Charge EtOAc (400 mL, 8 vol)and take sample for GC and KF analysis for t-butanol and water content,respectively (Note: Repeat distillation if t-BuOH content by GC is over0.2% or KF is over 0.1%. In this case, t-BuOH content was 0.77%;repeating distillation afforded 431 g of a solution containing 0.14%t-BuOH and KF 0.01%). To a reactor equipped with mechanical stirrer,thermocouple, reflux condenser and argon inlet was added the ethylacetate solution of the diol after distillation. To the reactor wasadded MsCl (23.40 mL, 301.39 mmol, 2.2 equiv) in one portion. Thesolution was stirred for 5 min and cooled to T_(batch)˜15° C. atT_(jacket)=0-5° C. Triethylamine (48 mL, 342.49 mmol, 2.5 equiv) wasadded dropwise via addition funnel ˜15-20 minutes, maintaining batchtemperature <25° C., forming a white suspension (Note: The addition isexothermic. In this case, internal temperature increased to −25° C. withT_(jacket)=5° C. An impurity has been observed to form at longeraddition times). The temperature was adjusted to T_(jacket)=20° C. andthe suspension stirred about 15 minutes and analyzed by UPLCMS. Thereaction was quenched by addition of 3% aqueous sodium bicarbonatesolution (250 ml, 5 vol). The mixture was stirred for about 15 minutesat 20-25° C. and then allowed to separate for about 15 minutes. Thelower aqueous layer was drained (Note: The recommended pH of the aqueouslayer is 8-9). Water (250 mL, 5 vol) was added. The mixture was stirredfor about 15 minutes at 20-25° C. and then allowed to separate for about15 minutes. The lower aqueous layer was drained (Note: The recommendedpH of the aqueous layer is 7-8). Ethyl acetate was distilled at 40-45°C. batch temperature and vacuum until about (˜250 mL, 5 vol) remained.Heptane (˜250 mL, 5 vol) was added slowly, maintaining batch temperatureat 40-45° C. The distillation was continued at 40-45° C. until (˜250 mL,5 vol) remained. Additional n-heptane (100 mL, 2 vol) was added slowlymaintaining temperature at 40-45° C. The slurry was cooled to 20-25° C.and stirred for at least 1 hour and filtered. The cake was washed withn-heptane (50 ml, 1 vol) and dried at 35-40° C. using full vacuum with aslow nitrogen bleed overnight to afford compound F6 in 90-95% yield.

di-tert-butyl1-(3-(2-((methylsulfonyl)oxy)ethyl)-3-(((methylsulfonyl)oxy)methyl)cyclobutyl)hydrazine-1,2-dicarboxylate

¹H-NMR (CDCl₃); δ 6.05 (br s, 1H), 4.68 (br s, 1H), 4.29 (t, J=6.4 Hz,2H), 4.24 (br s, 2H), 3.05 (s, 3H), 3.01 (s, 3H), 2.23 (br t, J=10 Hz,2H), 2.12 (br t, J=10 Hz, 2H), 2.04 (t, J=6.4 Hz, 2H), 1.49 (s, 9H),1.45 (s, 9H). ¹³C-NMR (CDCl₃); 156.3, 154.7, 81.7, 73.1, 66.3, 47.4,46.2, 37.6, 37.5, 36.8, 34.6, 34.1, 28.4, 28.3.

1.6. General Procedure for the Synthesis of Compounds of Formula II

To a reactor under inert atmosphere equipped with mechanical stirrer,thermocouple, reflux condenser and argon inlet was added benzylamine(125 mL, 1145.4 mmol, 5 equiv). The solution was stirred and heated to90-95° C. with T_(jacket)=100° C. A solution of compound F6 (120 g,229.08 mmol, 1.0 equiv) in THF (360 mL, 3 vol) was added in 3 equalportions, distilling the THF from each portion so the temperaturereached 90-95° C. before addition of the next portion (Note: Theaddition should be done in NLT 1 h. The internal batch temperature afterthe third addition may be 100-105° C.). The mixture was stirred at90-95° C. for at least 30 minutes and then analyzed by HPLC. Isopropanol(240 mL, 2 vol) was added over about 10 minutes (Note: the charge ratewas adjusted to control the batch temperature to 70-75° C. during theaddition). Water (240 mL, 2 vol) was then added over about 10 min (Note:the charge rate was adjusted to control the batch temperature to 70-75°C. during the addition). The batch was cooled to 60-65° C. and seeds ofcompound II (5 g in 20 mL water) were added. The batch was cooled to50-55° C. (Note: the batch will thicken. Adjust agitation rateaccordingly as needed to maintain adequate stirring. Add water from nextoperation if stirring becomes difficult). Water (480 mL, 4 vol) wasadded slowly over about 30 min keeping temperature at 50-55° C. Thebatch was cooled to 20-25° C. over about 3 hours and stirred for about 2hours and filtered. The reactor and filter cake was rinsed with 10%isopropanol/water (120 mL) followed by water (120 mL). The solids weredried at 50-55° C. using full vacuum with a slow nitrogen bleed for atleast 12 hours to afford compound II as an off-white solid in about 90%yield.

di-tert-butyl1-(6-benzyl-6-azaspiro[3.4]octan-2-yl)hydrazine-1,2-dicarboxylate

¹H-NMR (CDCl₃); δ 7.23-7.32 (m, 5H), 6.10 (br s, 1H), 4.52 (br s, 1H),3.60 (s, 2H), 2.55 (br s, 4H), 2.18 (br s, 2H), 2.07 (br s, 2H), 1.84(t, J=7.5 Hz, 2H), 1.47 (s, 9H), 1.44 (s, 9H). ¹³C-NMR (CDCl₃); 156.0,154.9, 139.3, 128.9, 128.4, 127.0, 81.2, 81.1, 66.3, 60.7, 53.8, 47.8,47.4, 40.3, 39.2, 38.0, 28.4, 28.3.

What is claimed is:
 1. A compound of formula (II):

wherein R3 is chosen from hydrogen, halogen, halo C1-4 alkyl, C1-4 alkyl, C1-4 alkoxy, —CN, halo C1-4 alkoxy, acyl, acyloxy, alkylaryl or cycloalkyl; and R4 is hydrogen, halogen, halo C1-4 alkyl, C1-4 alkyl, C1-4 alkoxy, aryloxy, cycloalkyl, alkylaryl; or an acceptable salt or hydrate thereof.
 2. A method making the compound of formula (II),

comprising the steps of: (i) Converting a compound of formula F to a compound of formula F1

(ii) Coupling of a compound of formula F1 with compound F2

to derive a compound of formula F7,

(iii) Convert the compound of formula F7 to a compound of Formula (II)

wherein R3 is chosen from hydrogen, halogen, halo C1-4 alkyl, C1-4 alkyl, C1-4 alkoxy, —CN, halo C1-4 alkoxy, acyl, acyloxy, alkylaryl or cycloalkyl; and R4 is hydrogen, halogen, halo C1-4 alkyl, C1-4 alkyl, C1-4 alkoxy, aryloxy, cycloalkyl, alkylaryl; or an acceptable salt or hydrate thereof. 